FDA Grants Pembrolizumab Priority Review for Frontline HNSCC

The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) alone or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy as a first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).1

The application is based on the data from the phase III KEYNOTE-048 trial, in which pembrolizumab alone led to a significant improvement in overall survival (OS) compared with standard chemotherapy in patients whose tumors expressed PD-L1 with a combined positive score (CPS) ≥20 and CPS ≥1.2 An OS improvement was also seen with the combination of pembrolizumab and chemotherapy in the overall patient population.

Under the Prescription Drug User Fee Act, the FDA will decide on the sBLA by June 10, 2019, Merck (MSD), the developer of the PD-1 inhibitor, reported in a press release.

“Head and neck cancer remains a challenging and devastating disease, and newly diagnosed patients are in need of improved treatment options,” said Jonathan Cheng, MD, vice president, clinical research, Merck Research Laboratories. “Merck continues to make meaningful advances in the treatment of head and neck cancer, and we look forward to working with the FDA to bring these important new options to patients in the first-line setting.”

Additionally, KEYNOTE-048 is the confirmatory trial for the phase Ib KEYNOTE-012 trial, which was the basis for the accelerated approval in August 2016 for single-agent pembrolizumab for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

The open-label, randomized, phase III KEYNOTE-048 study evaluated whether pembrolizumab could prolong survival and slow disease progression versus the EXTREME regimen—platinum-based chemotherapy with cisplatin or carboplatin, 5-FU, and cetuximab (Erbitux)—in the recurrent or metastatic setting. A total 882 patients were randomized in a 1:1:1 ratio to either standard EXTREME treatment (cetuximab at 400 mg/m2 loading dose followed by 250 mg/m2 weekly, plus cisplatin at 100 mg/m2 or carboplatin AUC 5 every 3 weeks, plus 5-FU at 1000 mg/m2 daily on day 1 through 4 of each 3-week cycle for a maximum of 6 cycles; n = 300); single-agent pembrolizumab at 200 mg every 3 weeks for 2 years (n = 301); or a combination of pembrolizumab and platinum-based chemotherapy with 5-FU (n = 281). Treatment was administered until unacceptable toxicity or progressive disease.

Patients enrolled on the study had squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx; had not received prior chemotherapy or systemic therapy for their recurrent or metastatic disease; and had good ECOG performance status with tissue available for PD-L1 testing. Patients were stratified by PD-L1 expression, p16 status, and ECOG performance status.

The primary endpoints were progression-free survival (PFS) and OS in patients with a PD-L1 CPS ≥20, ≥1, and in all patients enrolled. The data cutoff date was June 13, 2018, with a minimum follow-up of 17 months.

Results of the study, which were presented at the 2018 ESMO Congress, showed that in patients with PD-L1 CPS ≥20 (n = 255), the median OS was 14.9 months versus 10.7 months in those who received pembrolizumab alone versus EXTREME (HR, 0.61; 95% CI, 0.45-0.83; P = .0007), respectively, and the 2-year OS rate was 38% versus 22%. There was no difference in PFS between the 2 arms (HR, 0.99; 95% CI, 0.75-1.29; P = .5).

Moreover, the ORRs were 23.3% and 36.1% with pembrolizumab and standard therapy, respectively; however, the median DOR was longer with the PD-1 inhibitor at 20.9 months versus 4.5 months.

For patients with a PD-L1 CPS ≥1 (n = 512), the results were similar, in which the median OS for pembrolizumab monotherapy versus EXTREME was 12.3 months versus 10.3 months, respectively (HR, 0.78; 95% CI, 0.64-0.96; P = .0086); the 2-year OS rates were 30% versus 19%. The ORR was 19.1% with pembrolizumab and 34.9% with standard therapy, yet the median DOR was again longer with pembrolizumab at 20.9 months and 4.5 months, respectively. There was no difference in PFS between the 2 groups (HR, 1.16; 95% CI, 0.75-1.29).